Ultraviolet phototherapy is a first-line treatment

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1 Review Acitretin Plus UVB Phototherapy in the Treatment of Psoriasis Bridgit V. Nolan; Brad A. Yentzer, MD; Steven R. Feldman, MD, PhD Acitretin frequently is used in conjunction with UVB phototherapy. Home-based phototherapy is an important therapeutic option that offers greater convenience to patients. We conducted a review of the literature on acitretin and home-based phototherapy in the treatment of psoriasis with a focus on the reported efficacy, safety, cost, and practical use considerations associated with combination therapy. Acitretin plus UVB phototherapy is more efficacious than either treatment alone. Adverse events reported were similar between office-based and home-based phototherapy treatments. Acitretin is not appropriate for women of COS childbearing potential. DERM Patients generally are more satisfied with home-based phototherapy than office-based phototherapy. Dermatologists should consider acitretin plus homebased phototherapy as a first-line treatment option for appropriately selected patients with psoriasis. Ultraviolet phototherapy is a first-line treatment option for extensive psoriasis often Ms. Nolan is a medical student, and Dr. Yenzter is the senior clinical research fellow, Department of Dermatology; Dr. Feldman is Director, used in conjunction with the systemic Center for Dermatology Research, Departments of Dermatology, retinoid acitretin. Either broadband (BB) Pathology, and Public Health Sciences; all are from Wake Forest or narrowband (NB) UVB phototherapy University School of Medicine, Winston-Salem, North Carolina. can be used. The standard approach for the administration of UVB phototherapy is to provide treatment in the Dr. Feldman is a consultant for, has received grant support from, and is a speaker for Abbott Laboratories; Amgen Inc; physician s office, which is a safe and highly effective Biogen Idec; Bristol-Myers Squibb; Centocor Ortho Biotech Inc; treatment. 1,2 However, office-based phototherapy can Galderma SA; Stiefel Laboratories, Inc; and Warner Chilcott; be inconvenient, costly, and burdensome. Home-based is a consultant for and has received research support from phototherapy is convenient and inexpensive, and is Genentech, Inc, and PhotoMedex, Inc; is a speaker for 3M; associated with both a good adherence rate and high Genentech, Inc; and Novartis AG; has received grant support patient satisfaction. 3 from 3M; Aventis Pharmaceuticals Inc; CORIA Laboratories, Acitretin frequently is used in combination with either Ltd; National Biological Corporation; Ortho-McNeil-Janssen systemic medications or phototherapy. 4 The combination Pharmaceuticals, Inc; PharmaDerm, a Division of Nycomed US, of acitretin plus UVB phototherapy is more effective than Inc; and F. Hoffmann-La Roche Ltd; has received research grants either therapy alone. This article reviews the use of acitretin in conjunction with home-based UVB phototherapy in from the Dermatology Foundation and the American Society for Dermatologic Surgery; has received research support from the treatment of psoriasis. Novartis AG; and has stock option in PhotoMedex, Inc. Ms. Nolan and Dr. Yentzer report no conflicts of interest. Methods Correspondence: Steven R. Feldman, MD, PhD, Department of A review of the literature on combination therapy with Dermatology, Wake Forest University School of Medicine, acitretin and home-based UVB phototherapy for the treatment of psoriasis was conducted using MEDLINE/PubMed. Medical Center Blvd, Winston-Salem, NC (sfeldman@wfubmc.edu). The following search terms were employed: combination Vol. 23 No. 3 MARCH 2010 Cosmetic Dermatology 137

2 therapy, phototherapy, home phototherapy, acitretin, and psoriasis. The efficacy, safety, cost, and practical use considerations associated with combination therapy involving acitretin and home-based UVB phototherapy were investigated. Clinical Data Acitretin Plus Standard Office-Based Phototherapy Acitretin administered as a monotherapy in doses of 50 mg daily is moderately effective in the treatment of psoriasis, but is associated with substantial dose-related adverse effects, including hair loss, abnormal nail formation, pyogenic granulomas, and dyslipidemia. 5 When used alone, standard phototherapy entails 2 to 3 sessions per week for a period of 12 weeks to achieve therapeutic results. Acute adverse events related to phototherapy include erythema, blistering, and dryness of the skin. Additionally, total cumulative UVB dose-related effects include photocarcinogenesis and photoaging of the skin. 1 However, it should be noted that unlike psoralen plus UVA, evidence for increased incidence of skin cancers with UVB phototherapy is lacking. 6-8 Combination therapy with acitretin plus UVB phototherapy offers multiple advantages over the use of either modality as a sole intervention in the treatment of psoriasis. Acitretin enhances the potency of phototherapy, thereby reducing the necessary dose of UV light and acitretin monotherapy. 12 Additionally, participants who received combination therapy required a lower dose of UVB phototherapy and fewer treatments with UVB phototherapy to achieve clearance, which lead to a reduction in total cumulative UVB dose of approximately 20%. 12 Combination acitretin plus UVB phototherapy is effective in the treatment of psoriasis that is refractory to either standard phototherapy or acitretin as the sole treatment modality. 1 Acitretin Plus Home-Based Phototherapy Compared to standard office-based outpatient phototherapy, home-based phototherapy has similar efficacy as assessed by reduction in PASI and self-administered PASI scores, proportion of participants reaching PASI 50 and self-administered PASI 50 scores, and increase in quality of life and safety as assessed by acute adverse events and total cumulative UV dose. 13 There have been few studies to assess the efficacy of combination therapy using acitretin and home-based phototherapy (Table 1) The combination of home-based NB-UVB phototherapy (3 sessions/wk with increased exposure time based on Fitzpatrick skin type and response to treatment) and lowdose acitretin (25 mg/d with dose adjustment as needed) in participants with moderate to severe plaque psoriasis demonstrated reduction in PASI scores with overall mean improvement in PASI scores of 22%, attainment of PASI 50 in 4 participants, and a PASI 75 in 0 participants the treatment time for clearing of psoriatic lesions. 9 The by week 12 (N527). 14 Additional outcomes included reduction in total cumulative UVB dose associated with increased quality of life as measured by the Dermatology combination therapy reduces the risk of late-appearing Life Quality Index and high satisfaction with treatment. adverse events, including photocarcinogenesis and photoaging. 10 Conversely, the use of phototherapy appears the study duration was short and a plateau PASI improve- The true efficacy of this combination might be higher, as to confer a retinoid dose-sparing effect, thus potentially ment was not reached during the 12-week period. diminishing the side effects and improving tolerability Furthermore, participants in this particular study stood of treatment with acitretin inches away from the UV lamps instead of the recommended 6 inches, thereby receiving only a fraction of the Combination therapy with acitretin plus UVB phototherapy results in greater and more rapid improvement standard UV dose. Measured adherence to combination in psoriatic lesions. In a 12-week, placebo-controlled, acitretin and home-based NB-UVB phototherapy in participants with moderate to severe psoriasis demonstrated clinical trial participants undergoing combination therapy (acitretin 50 mg/d plus UVB phototherapy) achieved 75% good adherence to home-based phototherapy with the improvement in their Psoriasis Area Severity Index (PASI) average number of sessions constant at 2 to 3 sessions scores compared to 35% improvement in participants per week while adherence to oral acitretin decreased treated with only UVB phototherapy and 42% improvement in participants who received acitretin mono- affect adherence to either treatment modality. 15 A recent steadily. Side effects were well tolerated and did not therapy. 10 Another clinical trial of combination therapy study of low-dose acitretin (25 mg/d) in conjunction with low-dose acitretin ( mg/kg daily) plus with commercial tanning bed therapy (4 5 sessions/wk) UVB phototherapy in 41 participants with plaque-type in the treatment of chronic plaque-type psoriasis demonstrated good efficacy. 16 In the retrospective study, clear- psoriasis demonstrated disease clearance in 89% (8/9) of participants treated with combination therapy, ance or near clearance was achieved in 83%, moderate 62.5% (20/32) of participants treated with UVB phototherapy, and 23% (2/9) of participants treated with participants (n523). Additionally, participants improvement in 9%, and no improvement in 9% of reported 138 Cosmetic Dermatology MARCH 2010 Vol. 23 No. 3

3 Table 1 Clinical Trials Involving Combination Therapy With Acitretin and Home-Based Phototherapy Participants Methods Results Limitations Participants with Following a 4-wk washout period for systemic PASI score at week 12 was 13.9, a decrease from Small study population, short moderate to severe therapies, treatment with acitretin (25 mg/d baseline of 18.6, constituting a 22% reduction. treatment duration, conservative plaque-type with dose modification as needed) and home- Four participants achieved PASI 50, and 0 UVB dose (12-in vs 6-in distance), psoriasis (N527) 14 based NB-UVB phototherapy (flat-panel Pansol II reached PASI 75 by the end of the study. Mean and escalation of exposure time. unit) 3 times/wk with increasing exposure time DLQI improved from 11.9 to 7.0 over the 12-wk based on Fitzpatrick skin type and response interval and satisfaction with treatment was high. Plateau PASI was not achieved Adverse effects: In general, the treatment was well tolerated, with mild alopecia and increased photosensitivity in a few participants. Elevated triglyceride levels were observed in several participants, necessitating a decrease in acitretin dose to 10 mg daily in 4 participants. by the end of the study, suggest- ing that ultimate efficacy may be higher. to treatment) was carried out over a 12-wk period. The use of stable topical treatments and emollients was permitted. Participants with Adherence to combination therapy with Mean adherence to acitretin decreased steadily Small study population, loss moderate to severe acitretin (10 25 mg/d) and home-based from 93.6% initially to 54.4% at wk 12 (slope, of follow-up, and short duration psoriasis (N527) 15 NB-UVB phototherapy (3 times/wk) for uses/wk), with average adherence ranging of study. 12 wk was assessed. from 2.5 to 7 uses/wk among study participants (n522). Mean adherence to home-based phototherapy was steady at 2 to 3 uses/wk, with a decrease from 2.4 uses/wk initially to 2.1 uses/wk at week 12. Average adherence ranged from 0.17 to 3.5 uses/wk among study participants (n516). Adverse effects: No significant phototoxic episodes were reported in any of the participants. Participants with For the retrospective study, medical record review In the retrospective study, 83% experienced The prospective trial was moderate to severe and participant surveys regarding compliance, clearance or near clearance, 9% had moderate limited by lack of controls and plaque-type psoriasis satisfaction, and global assessment of improvement, and 9% had no improvement blinding and small study (N526 in the retro- improvement were conducted. (n523). Satisfaction with treatment was high. population. spective study; N517 in the prospec- For the prospective trial, combination therapy In the prospective trial, PASI and National Psoriasis tive trial) 16 with acitretin (25 mg/d) and commercial tanning bed Foundation scores demonstrated an average exposure (mean UVB output of 4.7% 4 to 5 times/wk) reduction of 78.6% and 79%, respectively. PASI 50 was carried out over a 12-wk interval. and PASI 75 were achieved by 76% and 59%, respectively. Adverse events were mild to moderate. Abbreviations: NB, narrowband; PASI, Psoriasis Area and Severity Index; DLQI, Dermatology Life Quality Index. Vol. 23 No. 3 MARCH 2010 Cosmetic Dermatology 139

4 high satisfaction with combination acitretin and tanning bed therapy. In the prospective trial, PASI 50 and PASI 75 were achieved in 76% (13/17) and 59% (10/17) participants, respectively, and there were average reductions of 78.6% in PASI and 79% in National Psoriasis Foundation scores compared with baseline scores following 12 weeks of combination therapy. Treatment was generally well tolerated and adverse events were mild to moderate. 16 Cost Considerations There is wide variability in the cost of and response to treatment in patients with psoriasis and additional costs may result from treatment failures. 17 The cost of acitretin monotherapy in 2004 was estimated at $400 per month. 18 The concomitant use of phototherapy, which confers a retinoid dose-sparing effect, may help lower the cost of long-term treatment for patients treated with acitretin. It also may help reduce costs associated with treatment failures by improving cases of psoriasis resistant to either treatment modality as the sole intervention. Conversely, low-dose acitretin increases the potency of phototherapy, thereby reducing the number of treatments required for clearing. 10 Fewer phototherapy sessions are required, thus reducing treatment time and number of phototherapy treatment sessions. 9 This may lead to better patient satisfaction and more efficient utilization of healthcare resources. The use of home-based phototherapy requires the purchase of a unit, which has associated initial and receiving combination acitretin plus UVB phototherapy. maintenance costs. However, home-based phototherapy Follow-up laboratory tests are performed every month remains the most cost-effective option compared with while dose adjustments are being made and continued alternatives (including methotrexate, biologic agents, thereafter as clinically indicated. Acitretin is not recommended for women of childbearing age who wish to acitretin monotherapy, and psoralen plus UVA) for the treatment of patients with psoriasis. 3 From the viewpoint of insurers, a 3-month trial of home-based photo- discontinuation of treatment. For women of childbear- become pregnant during or within 3 years following therapy can yield annual savings ranging from $2110 to ing age, 2 negative pregnancy tests prior to initiating acitretin treatment and monthly tests thereafter $21,610 per patient compared with standard office-based outpatient phototherapy, treatment with biologic agents, are required. 23 or both. 19 Practical Use Considerations Timing Initiation of Acitretin Therapy For combination therapy with acitretin plus UVB phototherapy, low-dose acitretin (usual dose, 25 mg/d) typically is administered as a single agent 1 to 2 weeks prior to the initiation of UVB phototherapy treatment. This schedule allows for minimal erythema dose (MED) testing while the patient is on a stable dose of acitretin, which frequently reduces the MED required to achieve the desired effect. UVB phototherapy treatments are then added to the regimen and this combination is continued for at least 4 more weeks. 20 For patients who are treated with NB-UVB phototherapy in conjunction with oral acitretin, the initial NB-UVB phototherapy dose is 50% of the MED. For combination regimens that involve oral acitretin and BB-UVB phototherapy, the initial BB-UVB phototherapy dose is calculated according to Fitzpatrick skin type (Table 2). The dose of acitretin is adjusted according to clinical response, which usually involves a dose reduction during the first 2 months of treatment. 22 For patients who are initiated on combination therapy who have already undergone induction of UVB phototherapy treatment, the UVB phototherapy dose should be reduced by 50% prior to the initiation of acitretin. Dose Adjustments Because combination therapy results in a retinoid dosesparing effect, doses of acitretin used are usually 10 to 25 mg daily. Due to thinning of the stratum corneum associated with acitretin use, UVB phototherapy doses should be reduced by 50% to avoid phototoxicity and dosimetry should be increased gradually with additional increments of 50% of the usual amount. 20 Laboratory Monitoring Baseline laboratory tests, including complete blood cell count, fasting lipid panel, and liver function tests should be performed on all patients with psoriasis Discussion The benefits of combination therapy with acitretin plus UVB phototherapy are numerous and include quicker and more complete resolution of psoriatic lesions with lower doses of both treatment modalities and thus lower potential for adverse effects and toxicity. Combination therapy with acitretin plus home-based phototherapy is a good option for patients with psoriasis who live a long distance from a treatment center and for those who find office-based phototherapy burdensome and inconvenient. Several UVB phototherapy device manufacturers offer full-body, single-panel, multiplepanel, and hand-held units for both office-based and 140 Cosmetic Dermatology MARCH 2010 Vol. 23 No. 3

5 Table 2 Protocols for Combination Therapy With Acitretin and Home-Based UVB Phototherapy 21 Acitretin Dosage UVB Dosage Treatment Combination and Timing and Timing Modification Low-dose acitretin Starting dose is 25 mg/d (may be Initial BB-UVB dose is determined Acitretin: Dose of acitretin plus BB-UVB adjusted by physician according based on Fitzpatrick skin type: is adjusted according to phototherapy to other factors) and is typically (type 1, 20 mj/cm 2 ; type II, clinical response. Decrease initiated 1 to 2 wk prior to 25 mj/cm 2 ; type III, 30 mj/cm 2 ; in dose of acitretin often initiation of BB-UVB photo- type IV, 40 mj/cm 2 ; type V, occurs during the first therapy treatments. 50 mj/cm 2 ; type VI, 60 mj/cm 2 ). 2 mo of treatment. The frequency of BB-UVB photo- Broadband-UVB phototherapy treatments in association therapy: BB-UVB dose is with low-dose acitretin adjusted according to for psoriasis is typically 3 to clinical response (redness, 5 times/wk. light pink color, tenderness), and dose escalation is typically 50% of the If low-dose acitretin is initiated regular amount. after induction of BB-UVB phototherapy treatment, dose of BB-UVB should Do Not be reduced Copy by 50% and should not be increased for at least 2 wk. Low-dose acitretin Starting dose is 25 mg/d (may be After 1 to 2 wk of acitretin Acitretin: Dose of acitretin plus NB-UVB adjusted by physician according to therapy, perform MED testing is adjusted according to phototherapy other factors) and is typically in the lower lumbar or sacral clinical response. Decrease begun 1 to 2 wk prior to the area. The initial dose of NB-UVB in dose of acitretin often initiation of NB-UVB photo- will be 50% of the MED. occurs during the first therapy treatments. 2 mo of treatment. Abbreviations: BB, broadband; NB, narrowband; MED, minimal erythema dose. The frequency of NB-UVB phototherapy using MED Narrowband-UVB phototreatments for psoriasis is therapy: NB-UVB dose is typically 3 times/wk. adjusted according to clinical response (redness, light pink color, If acitretin is initiated after tenderness), and dose induction of NB-UVB photo- escalation is calculated therapy treatment, dose of according to treatment NB-UVB should be reduced number (for treatments by 50% and should not be 1 20, increase by 10% of, increased for at least 2 wk. MED; for treatments 21 and over, dose escalation is determined by physician). Vol. 23 No. 3 MARCH 2010 Cosmetic Dermatology 141

6 Table 3 Phototherapy Equipment Manufacturers a Company Equipment Web Site Phone National Biological Full-body, hand-held, and localized Corporation BB-UVB and NB-UVB units Mercantile Road Beachwood, OH Daavlin Full-body hand/foot/scalp BB-UVB West Bement Street and NB-UVB units PO Box 626 Bryan, OH UVBioTek Full-body, wrap-around, and single PO Box 430 panel systems plus hand/foot units 3 Depot Street with BB-UVB and NB-UVB Hudson Falls, NY Abbreviations: BB, broadband; NB, narrowband. a Table 3 lists several manufacturers of home-based phototherapy devices for sale in the United States, which can be found on the National Psoriasis Foundation Web site. 24 Table 3 represents a sample of phototherapy device manufacturers and is not comprehensive. home-based use (Table 3). It also is an attractive option for 2. Feldman SR, Koo JYM, Lebwohl MG, et al. The Psoriasis and Psoriatic Arthritis Pocket Guide: Treatment Algorithms and patients with concomitant infections or reduced immune Management Options. Portland, OR: National Psoriasis system functioning, for whom therapy with immunomodulators (biologics and methotrexate) may be contraindicated. 3. Yelverton CB, Kulkarni AS, Balkrishnan R, et al. Home Foundation; Adherence to treatment remains a problem in the successful management of patients with psoriasis. Combiriasis. Manag Care Interface. 2006;19(1):33-36, 39. ultraviolet B phototherapy: a cost-effective option for severe pso- 4. Kinney MA, Feldman SR. What s new in the management of psoriasis? G Ital Dermatol Venereol. 2009;144: nation treatment with acitretin plus UVB phototherapy produces better results, thus increasing patient satisfaction, decreasing burden of disease, and fostering better 5. Gupta AK, Goldfarb MT, Ellis CN, et al. Side-effect profile of adherence to treatment. Although an absolute increase in acitretin therapy in psoriasis. J Am Acad Dermatol. 1989;20: skin cancer risk has not been demonstrated, 6,7 the theoretical increased risk weighs heavily in the minds of some Weischer M, Blum A, Eberhard F, et al. No evidence for increased skin cancer risk in psoriasis patients treated with broadband or patients and physicians. The use of retinoids in conjunction with phototherapy may protect against this theoreti- Derm Venereol. 2004;84: narrowband UVB phototherapy: a first retrospective study. Acta cal carcinogenicity by reducing total cumulative UV dose, 7. Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J Dermatol. 2005;44: exerting tumor-suppressive effects, and reversing skin cancer through the differentiation of atypical keratinocytes. 21,24 The use of combination therapy with acitretin narrowband UVB (TL-01) phototherapy: early follow-up data. Br J 8. Man I, Crombie IK, Dawe RS, et al. The photocarcinogenic risk of and home-based phototherapy should be encouraged as Dermatol. 2005;152: a first-line treatment for patients with extensive psoriasis. 9. Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of acitretin in combination with UV-B in the treatment of severe psoriasis. Arch Dermatol. 1990;126: References 10. Lowe NJ, Prystowsky JH, Bourget T, et al. Acitretin plus 1. Spuls PI, Rozenblit M, Lebwohl M. Retrospective study of the UVB therapy for psoriasis. Comparisons with placebo plus efficacy of narrowband UVB and acitretin. J Dermatolog Treat. UVB and acitretin alone. J Am Acad Dermatol. 1991;24: 2003;14(suppl 2): Cosmetic Dermatology MARCH 2010 Vol. 23 No. 3

7 11. Lebwohl M, Menter A, Koo J, et al. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol. 2004;50: Iest J, Boer J. Combined treatment of psoriasis with acitretin and UVB phototherapy compared with acitretin alone and UVB alone. Br J Dermatol. 1989;120: Koek MB, Buskens E, van Weelden H, et al. Home versus outpatient ultraviolet B phototherapy for mild to severe psoriasis: pragmatic multicentre randomised controlled non-inferiority trial (PLUTO study). BMJ. 2009;338:b Yelverton CB, Yentzer BA, Clark A, et al. Home narrowband UV-B phototherapy in combination with low-dose acitretin in patients with moderate to severe psoriasis. Arch Dermatol. 2008;144: Yentzer BA, Yelverton CB, Pearce DJ, et al. Adherence to acitretin and home narrowband ultraviolet B phototherapy in patients with psoriasis. J Am Acad Dermatol. 2008;59: Carlin CS, Callis KP, Krueger GG. Efficacy of acitretin and commercial tanning bed therapy for psoriasis. Arch Dermatol. 2003;139: Pearce DJ, Nelson AA, Fleischer AB, et al. The costeffectiveness and cost of treatment failures associated with systemic psoriasis therapies. J Dermatolog Treat. 2006;17: Pearce DJ, Thomas CG, Fleischer AB Jr, et al. The cost of psoriasis therapies: considerations for therapy selection. Dermatol Nurs. 2004;16: , Yentzer BA, Yelverton CB, Simpson GL, et al. Paradoxical effects of cost reduction measures in managed care systems for treatment of severe psoriasis. Dermatol Online J. 2009;15(4): Lebwohl M. Acitretin in combination with UVB or PUVA. J Am Acad Dermatol. 1999;41(3, pt 2):S22-S Levine N. Role of retinoids in skin cancer treatment and prevention. J Am Acad Dermatol. 1998;39(2, pt 3):S62-S Zanolli MD, Feldman SR. Phototherapy Treatment Protocols: For Psoriasis and Other Phototherapy Responsive Dermatoses. London, England: Taylor & Francis; Soriatane (acitretin) [package insert]. Coral Gables, FL: Stiefel Laboratories, Inc; National Psoriasis Foundation Web site. /home/. Accessed May Lebwohl M, Tannis C, Carrasco D. Acitretin suppression of squamous cell carcinoma: case report and literature review. J Dermatolog Treat. 2003;14(suppl 2):3-6. n Vol. 23 No. 3 MARCH 2010 Cosmetic Dermatology 143